The enhanced utilization of native L-Asparaginase (L-Asp) aims to improve treatment outcomes for adult patients with non-Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL). In this MRD2014 study, we modified our protocol to include an augmented dose of native L-Asp. Compared to former MRD2008, the total dose of L-Asp was raised from 36,000 U/m2 to 232,000 U/m2 in patients aged 16–35, and from 36,000 U/m2 to 132,000 U/m2 in patients aged 36–65.Adult ALL patients were enrolled between January 2014 and December 2019 based on the following eligibility criteria: non-L3 ALL, 16–65 years of age, Eastern Cooperative Oncology Group performance status of 0–2, and adequate liver and kidney function (serum bilirubin, ≤ 2.0 mg/dl and serum creatinine, ≤ 2.0 mg/dl). ResultsThe median follow-up time was 1128 days (range, 35–2400 days). A total of 81 non-Ph ALL patients (40 males and 41 females; median age 39 years, range 16 to 64 years) in whom MRD status was assessed were included. Complete remission (CR) was achieved in 72 patients (89%). The probability of three-year event-free survival (EFS) and overall survival (OS) in these patients was 55% (95%CI 43–65) and 72% (95%CI 61–81), respectively.The outcomes for patients aged 16–35 demonstrated remarkable improvement. The three-year EFS of MRD2008, at 45% (95%CI 27–62), significantly increased to 71% (95%CI 52–85) for MRD2014 (p = 0.038). Our study unequivocally demonstrated the beneficial effects of augmented use of L-Asp in this adolescent and young adult (AYA) population.This study was registered with the UMIN Clinical Trials Registry (UMIN-CTR), number UMIN000012382.